Copolymer-1, also known as glatiramer acetate and marketed under the tradename Copaxone.RTM., comprises the acetate salts of polypeptides containing L-glutamic acid, L-alanine, L-tyrosine and L-lysine. The average molar fraction of the amino acids are 0.141, 0.427, 0.095 and 0.338, respectively, and the average molecular weight of copolymer-1 is between 4,700 and 11,000 daltons. It is a non-autoantigen which has been demonstrated to suppress experimental allergic encephalomyelitis (EAE) induced by various encephalitogens including mouse spinal cord homogenate (MSCH) which includes all myelin antigens, such as myelin basic protein (MBP) (Sela M et al., Bull Inst Pasteur (1990) 88 303-314), proteolipid protein (PLP) (Teitelbaum D et al., J Neuroimmunol (1996) 64 209-217) and myelin oligodendrocyte glycoprotein (MOG) (Ben-Nun A et al., J Neurol (1996) 243 (Suppl 1) S14-S22) in a variety of species. EAE is an accepted model for multiple sclerosis.
Copolymer-1 has been demonstrated to be active when injected subcutaneously, intra-peritoneally, intravenously or intramuscularly (D. Teitelbaum et al., Eur. J. Immunol. (1971) 1:242-248; D. Teitelbaum et al., Eur. J. Immunol. (1973) 3:273-279).
In phase III clinical trials, daily subcutaneous injections of copolymer-1 were found to slow progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (K. P. Johnson, Neurology (1995) 1:65-70). Copolymer-1 therapy is presently limited to its daily subcutaneous administration.
Currently, all specifically approved treatments of multiple sclerosis involve self-injection of the active substance. Frequently observed injection-site problems include irritation, hypersensitivity, inflammation, pain and even necrosis (in the case of at least one interferon .beta. 1-B treatment) and a low level of patient compliance. Therefore, an alternative method of administration is desirable.
EP Patent 359,783 discloses the treatment of autoimmune diseases by oral administration of autoantigens. It discloses the oral administration of MBP for treatment of multiple sclerosis. Oral administration of an autoantigen has been termed "oral tolerance."
PCT International Application Publication Nos. WO 91/12816, WO 91108760, and WO 92/06704 all disclose the treatment of other autoimmune diseases using the "oral tolerance" method with a variety of autoantigens. However, none of these references disclose the treatment of multiple sclerosis by the oral administration of non-autoantigen copolymer-1. The contents of all these patents and all literature references referred to above are hereby incorporated by reference in their entirety.
It is, therefore, an object of the present invention to provide a method for treating multiple sclerosis by oral administration of copolymer-1 through ingestion or inhalation.